ABSTRACT Alzheimer?s disease (AD) has tremendous public health impacts and is associated with enormous costs to patients, their caregivers, and society as a whole. Environmental factors may be important in the development and progression of AD with recent research demonstrating that air pollutant exposure late in life contributes to lower cognitive performance and faster cognitive decline in older populations. At the same time, the neighborhood social environment (NSE), specifically neighborhood socioeconomic status and neighborhood social capital, has been linked to improved cognitive performance and may provide resilience to these effects. These studies highlight an urgent need to examine air pollutant and NSE impacts in cohorts in which AD is rigorously and prospectively ascertained, evaluate pathways underlying associations, and investigate markers of susceptibility and resilience. The Ginkgo Evaluation of Memory Study (GEMS) was a randomized trial designed to evaluate the efficacy of Ginkgo biloba supplements in lowering risk of incident AD and provides an extraordinarily rich resource of clinical trial data for a study of the NSE and air pollution, an environmental exposure with demonstrated cardiovascular and respiratory effects but whose relationship with AD is, as of yet, unknown. Between 2000 and 2008, GEMS followed over 3,000 participants aged 75 and older living in four communities in the United States for AD, regularly conducted comprehensive cognitive assessments, collected information on other factors including cardiovascular disease and, in a subset of the population, ascertained accumulation of amyloid-?, the pathological hallmark of AD, using PET brain imaging. Detailed residential histories throughout follow-up are available for GEMS participants from which we can ascertain measures of the NSE and estimate exposure to various air pollutants using already developed state-of-the art models of air pollutant exposure. We also will obtain residential histories up to 20 years prior to enrollment in GEMS, enabling the examination of multiple exposure windows of importance in the effects of air pollutants and the NSE on cognition in older adults. Specifically, we propose to investigate the impact of air pollutant exposures and the NSE on (1) incident AD and cognitive decline, (2) the progression to AD and cognitive trajectories in participants with mild cognitive impairment at study entry, and (3) amyloid-? deposition, which was ascertained in a subset of GEM study participants. We will investigate cardiovascular disease and depression as potential mediators of the effects of air pollutants on AD risk. Finally we will examine the interaction between NSEs and air pollution to assess resilience or exacerbation of AD outcomes. Our study will provide insight into pathways important in the effects of air pollutants and the NSE on the brain and inform strategies aimed at preventing, delaying the onset, and slowing the progression of a devastating disease affecting millions of Americans.